Obesity is fundamentally a disorder of energy balance. Adult body weight is normally maintained within a narrow range by neural and hormonal circuits which act to balance energy intake and expenditure. To accomplish this balancing act, the central nervous system senses and responds to changes in circulating metabolites, such as glucose and free fatty acids, and hormones, such as insulin and leptin. In humans and other mammals, these peripheral signals are integrated by neural circuits in the hypothalamus, which then coordinate responses via projections to other brain regions. One such feedback circuit, the melanocortin circuit in the arcuate nucleus of the hypothalamus, consists of neuropeptide Y (NPY)-expressing neurons, which promote feeding and decrease energy expenditure, and pro-opiomelanocortin (POMC)-expressing neurons, which inhibit feeding and increase energy expenditure. However, the downstream events of hormone sensing in NPY neurons are presently unclear. This project will investigate the acute changes in electrical activity of NPY neurons in response to leptin and insulin and the intracellular signalin pathway that may mediate these effects. Determining these pathways may reveal insights into how resistance to these signals occurs in obesity and type 2 diabetes. PUBLIC HEALTH RELEVANCE: The number of obese adults and children is increasing dramatically worldwide, driving parallel increases in the prevalence of type 2 diabetes mellitus, hypertension, liver disease, and other associated conditions. Fundamentally, obesity is a disorder of the neural and hormonal mechanisms that sense the quantity of stored energy and appropriately modify food intake and energy expenditure; a better understanding these mechanisms is required to develop new treatments that safely lower body weight and blood glucose. This project aims to reveal how the circulating hormones leptin and insulin regulate a component of the hypothalamic melanocortin system, a key neural circuit that controls body weight and energy expenditure.